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There are two key features to this manuscript. The first is the obvious linkage between the presence of excess Aβ and the accumulation of early-stage phospho-tau variants. This is the first observation that reducing Aβ may slow the rate of tau filament formation (assuming early forms progress to late forms of hyperphosphorylated tau). It is consistent with the earlier reports that elevating Aβ in tau transgenic mice increased phospho-tau levels. If the same holds true in AD brain, it suggests that amyloid lowering therapies are likely have benefit in slowing AD progression.

A second outcome of the study is it suggests that not only can Aβ be rapidly removed from the brain, but that it returns very rapidly, as well. What took 12 months to accumulate originally, returns within 45 days. This implies that in transgenic mice, the accumulated Aβ and early forms of phospho-tau pathology are likely in an equilibrium state, with the rate of production exceeding the rate of removal by some amount, and age contributing to an even greater disequilibrium between these processes. Modifying the steady-state conditions with antibodies (to increase removal) or secretase inhibitors (to reduce production) leads to shifts in the steady-state pool of these substances over days. Once the equilibrium conditions are restored after clearance of the antibody, the amyloid deposits reemerge at levels comparable to that at the time of the antibody injection. We observe a similar rapid recovery of Aβ deposits after removal by activating microglia with LPS injections into hippocampus (Herber et al., Experimental Neurology, in press).

While the structural modifications of amyloid deposits in AD brain make such rapid removal unlikely to be complete, the autopsy reports from the suspended vaccine trial argue that some of the deposited Aβ is removable. These are exciting results linking the βAPtist and tauist theologies and argue that disrupting the pathway leading to neurodegeneration at any point is likely to be useful in treating AD.

These are a series of beautifully done studies, which strongly support the Aβ cascade hypothesis. However, to fully understand the potential of Aβ reduction to alter the clinical course of Alzheimer’s disease, it would be important to know whether lowering Aβ improves cognitive function in APP/tau mice. Moreover, if it does, is the improvement in cognitive function transient or is it sustained? Finally, it would be interesting to identify the specific molecular form of Aβ responsible for inducing the accumulation of abnormally phosphorylated tau.

While the data presented using antibodies is consistent with results obtained in other studies, I find the data using the gamma-secretase inhibitor DAPT doubtful.
Oddo, et al., write "Using an alternative approach, we show that administration of the gamma-secretase inhibitor, DAPT, leads to similar results. Therefore, the finding that Abeta-based interventions successfully clear the tau pathology in these 3xTg-AD mice provides compelling evidence in support of the amyloid cascade hypothesis."
This result is very hard to believe. How can an acute injection of DAPT cause Abeta plaque disappearance (figure 10 in the paper)?
Linking the plaque disappearance from the use of antibodies or DAPT is stretching it. Chronic use of DAPT should prevent plaque formation and certainly not dissolve, as quickly as the authors report, Abeta plaques.
There was a poster at the AD conference which would suggest the DAPT data is also probably dodgy, or not as simple as it is presented (see "Inhibition of beta-amyloid production and clearance of senile plaques in transgenic mice" by Joanna L. Jankowsky1, Jason Wen2, Hilda H. Slunt2, Victoria Gonzales2, Nancy A. Jenkins3, Neal G. Copeland3, David R. Borchelt2,
Presentation Number: P2-038.)
In that paper, the authors concluded that amyloid plaque formation can be quickly arrested by inhibiting A-beta production. However, mature amyloid plaques are not rapidly cleared, and more time (as much as several months), or additional manipulations, may be required to reverse this pathology.
Otherwise, it is an excellent paper, as it clearly demonstrates that targeting Abeta seems the right thing to do (as opposed to going after tau) to find a cure for AD.

The paper from the LaFerla lab is most interesting, and extremely well done, which I have mentioned in recent interviews to other news outlets. However, I do not think the data in this paper resolve controversies about the validity of the amyloid cascade hypothesis, although there are important lessons to be learned from these elegant studies. For example, the paper indicates that it is possible to remove Aβ deposits with anti-Aβ antibodies, as also shown by others, but that this has no effect on established or fully formed AD-like NFTs composed of hyperphosphorylated tau proteins. On the other hand somatodendritic tau is reduced by clearing Aβ deposits with anti-Aβ antibodies, presumably through the proteasome, according to this study, but the significance of somatodendritic tau is not yet understood since it is not a marker of or diagnostic lesion for any brain disorder, and it is uncertain if somatodendritic tau has any deleterious effects or behavioral consequences in the mice studied here or would have any such effects in human beings. Finally, these studies appear to confirm what has been learned from the four postmortem studies of Elan vaccine patients to date which is that Aβ immune therapy can clear Aβ deposits in AD patients, but, as in the mice here, fully formed NFTs do not appear to be affected by this immune therapy. Thus, it may be necessary to have multiple treatment approaches to AD including those that are Aβ-centric and tau-centric.

The paper by Oddo et al published in Neuron 2004 is most interesting. Together with the earlier reports (Oddo et al., 2003a; Oddo et al., 2003b) the authors describe a “missing link” between Aβ-amyloid and Tau pathology in an animal model for Alzheimer's disease. It is particularly interesting that intraneuronal Aβ precedes Tau pathology and injection of anti-Aβ antibodies reverses intraneuronal Aβ “accumulation”. Upon single injection of anti-Aβ antibodies, intracellular Aβ was first cleared followed by somatodendritic Tau, however, accumulated (Gallyas stained) Tau pathology was not reversed. Such an animal model offers the possibility to answer fundamental questions in Alzheimer`s disease pathology.

It would be important to know for instance whether intraneuronal Aβ, somatodendritic and hyperphosphorylated Tau impairs neuron function in this mouse model, and whether age-dependent synapse and neuron loss occurs. We and others found that intraneuronal Aβ per se is not sufficient for neuron loss. All APP transgenic models we have studied so far, elicit intraneuronal Aβ staining. A striking neuron loss was only seen in two different APP/PS1 transgenic mouse models with an enhanced Aβ42 to Aβ ratio (Blanchard et al., 2003; Casas et al., 2004; Schmitz et al., 2004). Interestingly, the neuron loss was not correlated with any obvious Tau pathology.

Together with the observations from Oddo et al. it is important to note that intraneuronal Aβ triggers both neuron loss, Tau trafficking and phosphorylation. Clearance of plaques can be successfully achieved by immunotherapeutic approaches as shown by a number of reports. However, since there is no correlation between plaque load and neuron loss in APP/PS1 transgenic mice (Casas et al., 2004; Schmitz et al., 2004), the question is still open whether neuron loss can be prevented by active or passive immunization. Oddo et al (2004) have clearly shown that clearing the extracellular Aβ pool also reduces the intracellular Aβ pool. We and others assume that there is an equilibrium between these pools (and maybe between different intracellular pools). However, there is a lack of information on the nature of “aggregated” Aβ species (dimers, protofibrills…?) within neurons in transgenic mouse brain and the precise molecular events leading to neuron death in Alzheimer's disease. While immunotherapy against Aβ removes intra- and extracellular Aβ, the next step needs to be shown whether it helps to stop neuron death.

The paper by Oddo et al, published in Neuron 2004, reaffirmed my belief that Frank LaFerla and his group at UC Irvine will be (if they are not already) at the forefront when it comes to advancing our knowledge of AD. I also heard Dr. LaFerla's talk on this data at the recent Philadelphia meeting, and thought it was one of the best presentations I heard. In regard to the comments by Thomas Bayer, who correctly inferred that "while immunotherapy against Aβ removes intra- and extracellular Aβ, the next step needs to be shown whether it helps to stop neuron death," in a recent report published in JCI (Caspase-cleavage of tau is an early event in AD tangle pathology, 114: 121-130, 2004), it was reported that in 12-month 3xTg-AD mice, caspase-cleavage of tau is evident and colocalizes with both an early tangle marker (MC1) and intraneuronal Aβ in CA1 pyramidal neurons. However, in their most recent report in Neuron, Oddo et al. did not examine whether removal of intraneuronal Aβ by immunotherapy abrogated caspase cleavage of tau. Although the demonstration of caspase-cleaved tau in this mouse model is not definitive for apoptosis or neuronal death occurring, it can be inferred that the activation of caspases and cleavage of cellular proteins (such as tau) most likely contributes to neuronal demise. In this regard, it would have been interesting to examine if immunotherapy prevents caspase activation and cleavage of tau in 3xTg-AD mice.

Important and interesting work, but one question. What kind of mice would be a relevant control for 3XTg mice? Sarcastically speaking, transgenic expression of BSA may accelerate tau pathology in tau transgenic mice. Thus, there remains the danger that using 3XTg mice for drug screening might produce artifacts.